Atherosclerosis, the underlying cause of heart attack and stroke, is a major cause of death and suffering worldwide. The scavenger receptor BI (SR-BI) plays crucial roles in preventing atherosclerosis both by serving as a hepatic receptor for HDL cholesterol and by regulating macrophage cellular cholesterol homeostasis and survival in the arterial plaque. Recent studies have implicated SR-BI in cell survival by preventing apoptosis. Interestingly, our preliminary studies implicate a critical role for SR-BI in regulating autophagy, another key mechanism for promoting cell survival. Furthermore, our data suggest a novel role for SR-BI in mediating cell survival through the regulation of angiogenin, a RNase III enzyme that mediates tRNA cleavage to produce tRNA-derived smRNAs (tDRs), which promote cell survival through protein translation suppression and post- transcriptional repression of mRNA targets. Importantly, we have recently found that tDRs represent the most abundant class of smRNAs on HDL, as over 60% of smRNAs were aligned to tRNA loci in the reference genomes. Strikingly, our preliminary studies suggest that atherosclerotic vessels have increased levels of tDRs compared to healthy aortas. In Specific Aim 1, we will examine the hypothesis that SR-BI antagonizes atherogenesis by controlling authophagic flux to limit macrophage death and foam cell formation. In Specific Aim 2, we will examine the hypothesis that macrophage SR-BI promotes cell survival by specific tDR expression through regulation of angiogenin activity. In Specific Aim 3, we will define the impact of SR-BI regulation of HDL-tDR communication in atherosclerosis. Furthermore, we will examine the impact of SR-BI deficiency on the signature of tDRs on HDL from humans with both common and rare loss-of function-variants of the SCARB1 gene. In addition, we will examine the impact of these human SCARB1 loss-of function variants on autophagy in macrophages. A better understanding of what processes lead macrophages to export tDRs to HDL and how this contributes to atherogenesis will likely lead to the discovery of new mechanisms underlying atherosclerosis and the identification of novel drug targets. Our ultimate goal is to leverage these novel roles of SR-BI in regulating autophagy, angiogenin and tRNA-derived small RNAs for therapeutic gain in the prevention and treatment of dyslipidemia and atherosclerosis.